The proposed studies involve further investigations into the biochemical and behavioral effects of ring-substituted amphetamine derivatives, in particular, p-chloroamphetamine (PCA). Unlike amphetamine, PCA markedly reduces levels of 5-hydroxytryptamine (5HT) and tryptophan hydroxylase activity in the brains of rats and mice. Moreover, following a single dose of PCA to rats, but not mice, these remain maximally reduced for 2 weeks and recover slowly during the next few months. Because PCA disappears from rat brain with a half-life of 8.5 hours, its long-lasting action may be due to a toxic metabolite. In order to investigate this, a detailed examination of the biological disposition of PCA in both rats and mice is planned. This will include studies of the pattern of metabolites in rats and mice, the regional and subcellular distribution of the drug and its metabolites,and binding of the drug and/or metabolites to subcellular particles and macromolecules. Moreover, the effects of classical inducers and inhibitors of hepatic mixed function oxidase on the long-term toxic effect of PCA are being investigated. The motor effects of PCA are also of interest. They are similar to those of amphetamine except that tolerance to the former develops rapidly on repeated dosing. The neurochemical mechanisms mediating tolerance to the drug are being examined, and the possibility of cross-tolerance with other CNS stimulants and/or hallucinogens will be explored.